Inference of equivalence for the ratio of two normal means with unspecified variances.

Equivalence trials aim to demonstrate that new and standard treatments are equivalent within predefined clinically relevant limits. We focus on when inference of equivalence is made in terms of the ratio of two normal means. In the presence of unspecified variances, methods such as the likelihood-ratio test use sample estimates for those variances; Bayesian models integrate them out in the posterior distribution. These methods limit the knowledge on the extent to which equivalence is affected by variability of the parameter of interest. In this article, we propose a likelihood approach that retains the unspecified variances in the model and partitions the likelihood function into two components: F-statistic function for variances, and t-statistic function for the ratio of two means. By incorporating unspecified variances, the proposed method can help identify a numeric range of variances where equivalence is more likely to be achieved, which cannot be accomplished by current analysis methods. By partitioning the likelihood function into two components, the proposed method provides more inference information than a method that relies solely on one component. Using a published set of real example data, we show that the proposed method produces the same results as the likelihood-ratio test and is comparable to Bayesian analysis in the general case. In a special case where the ratio of two variances is directly proportional to the ratio of two means, the proposed method yields better results in inference about equivalence than either the likelihood-ratio test or the Bayesian method. Using a published set of real example data, the proposed likelihood method is shown to be a better alternative than current analysis methods for equivalence inference.

A randomized phase 1 pharmacokinetic trial comparing the potential biosimilar PF-05280014 with trastuzumab in healthy volunteers (REFLECTIONS B327-01).

AIMS: The pharmacokinetic (PK) similarity between PF-05280014, a proposed trastuzumab biosimilar, trastuzumab sourced from European Union (trastuzumab-EU) or from United States (trastuzumab-US) was evaluated. Safety and immunogenicity were also assessed. METHODS: In this phase 1, double-blind trial (NCT01603264), 105 healthy male volunteers were randomized 1:1:1 to receive a single 6 mg kg(-1) intravenous dose of PF-05280014, trastuzumab-EU, or trastuzumab-US, and evaluated for 70 days. Drug concentration-time data were analyzed by non-compartmental methods. PK similarity for the comparisons of PF-05280014 to each of trastuzumab-EU and trastuzumab-US, and trastuzumab-EU to trastuzumab-US were determined using the standard 80.00% to 125.00% bioequivalence criteria. RESULTS: Baseline demographics for the 101 subjects evaluable for PK were similar across all arms. The three products exhibited similar PK profiles with target-mediated disposition. The 90% CIs for the ratios of Cmax , AUC (0 , t last) and AUC(0,∞) were within 80.00% to 125.00% for all three pairwise comparisons. Adverse events (AEs) were similar across all arms with treatment-related AEs reported by 71.4%, 68.6% and 65.7% subjects in the PF-05280014, trastuzumab-EU, and trastuzumab-US arms, respectively. The most common AEs were infusion-related reactions, headache, chills, pyrexia and nausea. The AE term 'pyrexia' was numerically greater in the PF-05280014 arm. All post-dose samples, except 1, tested negative for anti-drug antibodies (ADA). CONCLUSIONS: This study demonstrates PK similarity among PF-05280014, trastuzumab-EU and trastuzumab-US. The safety and immunogenicity profiles observed for the three products in this study are consistent with previous reports for trastuzumab.

Covariate effect on constancy assumption in noninferiority clinical trials.

Noninferiority (NI) clinical trials are getting a lot of attention of late due to their direct application in biosimilar studies. Because of the missing placebo arm, NI is an indirect approach to demonstrate efficacy of a test treatment. One of the key assumptions in the NI test is the constancy assumption, that is, that the effect of the reference treatment is the same in current NI trials as in historical superiority trials. However, if a covariate interacts with the treatment arms, then changes in distribution of this covariate will likely result in violation of constancy assumption. In this article, we propose four new NI methods and compare them with two existing methods to evaluate the change of background constancy assumption on the performance of these six methods. To achieve this goal, we study the impact of three elements-(1) strength of covariate, (2) degree of interaction between covariate and treatment, and (3) differences in distribution of the covariate between historical and current trials-on both the type I error rate and power using three different measures of association: difference, log relative risk, and log odds ratio. Based on this research, we recommend using a modified covariate-adjustment fixed margin method.

Inference of bioequivalence for log-normal distributed data with unspecified variances.

Two drugs are bioequivalent if the ratio of a pharmacokinetic (PK) parameter of two products falls within equivalence margins. The distribution of PK parameters is often assumed to be log-normal, therefore bioequivalence (BE) is usually assessed on the difference of logarithmically transformed PK parameters (δ). In the presence of unspecified variances, test procedures such as two one-sided tests (TOST) use sample estimates for those variances; Bayesian models integrate them out in the posterior distribution. These methods limit our knowledge on the extent that inference about BE is affected by the variability of PK parameters. In this paper, we propose a likelihood approach that retains the unspecified variances in the model and partitions the entire likelihood function into two components: F-statistic function for variances and t-statistic function for δ. Demonstrated with published real-life data, the proposed method not only produces results that are same as TOST and comparable with Bayesian method but also helps identify ranges of variances, which could make the determination of BE more achievable. Our findings manifest the advantages of the proposed method in making inference about the extent that BE is affected by the unspecified variances, which cannot be accomplished either by TOST or Bayesian method.

Intramyocardial, autologous CD34+ cell therapy for refractory angina.

RATIONALE: A growing number of patients with coronary disease have refractory angina. Preclinical and early-phase clinical data suggest that intramyocardial injection of autologous CD34+ cells can improve myocardial perfusion and function. OBJECTIVE: Evaluate the safety and bioactivity of intramyocardial injections of autologous CD34+ cells in patients with refractory angina who have exhausted all other treatment options. METHODS AND RESULTS: In this prospective, double-blind, randomized, phase II study (ClinicalTrials.gov identifier: NCT00300053), 167 patients with refractory angina received 1 of 2 doses (1×10(5) or 5×10(5) cells/kg) of mobilized autologous CD34+ cells or an equal volume of diluent (placebo). Treatment was distributed into 10 sites of ischemic, viable myocardium with a NOGA mapping injection catheter. The primary outcome measure was weekly angina frequency 6 months after treatment. Weekly angina frequency was significantly lower in the low-dose group than in placebo-treated patients at both 6 months (6.8±1.1 versus 10.9±1.2, P=0.020) and 12 months (6.3±1.2 versus 11.0±1.2, P=0.035); measurements in the high-dose group were also lower, but not significantly. Similarly, improvement in exercise tolerance was significantly greater in low-dose patients than in placebo-treated patients (6 months: 139±151 versus 69±122 seconds, P=0.014; 12 months: 140±171 versus 58±146 seconds, P=0.017) and greater, but not significantly, in the high-dose group. During cell mobilization and collection, 4.6% of patients had cardiac enzyme elevations consistent with non-ST segment elevation myocardial infarction. Mortality at 12 months was 5.4% in the placebo-treatment group with no deaths among cell-treated patients. CONCLUSIONS: Patients with refractory angina who received intramyocardial injections of autologous CD34+ cells (10(5) cells/kg) experienced significant improvements in angina frequency and exercise tolerance. The cell-mobilization and -collection procedures were associated with cardiac enzyme elevations, which will be addressed in future studies.

Rate and time to develop first central line-associated bloodstream infections when comparing open and closed infusion containers in a Brazilian Hospital

The objective of the study was to determine the effect of switching from an open (glass or semi-rigid plastic) infusion container to a closed, fully collapsible plastic infusion container (Viaflex®) on rate and time to onset of central lineassociated bloodstream infections (CLABSI). An open-label, prospective cohort, active healthcare-associated infection surveillance, sequential study was conducted in three intensive care units in Brazil. The CLABSI rate using open infusion containers was compared to the rate using a closed infusion container. Probability of acquiring CLABSI was assessed over time and compared between open and closed infusion container periods; three-day intervals were examined. A total of 1125 adult ICU patients were enrolled. CLABSI rate was significantly higher during the open compared with the closed infusion container period (6.5 versus 3.2 CLABSI/1000 CL days; RR=0.49, 95 percentCI=0.26- 0.95, p=0.031). During the closed infusion container period, the probability of acquiring a CLABSI remained relatively constant along the time of central line use (0.8 percent Days 2-4 to 0.7 percent Days 11-13) but increased in the open infusion container period (1.5 percent Days 2-4 to 2.3 percent Days 11-13). Combined across all time intervals, the chance of a patient acquiring a CLABSI was significantly lower (55 percent) in the closed infusion container period (Cox proportional hazard ratio 0.45, p= 0.019). CLABSIs can be reduced with the use of full barrier precautions, education, and performance feedback. Our results show that switching from an open to a closed infusion container may further reduce CLABSI rate as well as delay the onset of CLABSIs. Closed infusion containers significantly reduced CLABSI rate and the probability of acquiring CLABSI.

A note on statistical analysis of organ weights in non-clinical toxicological studies.

Statistical comparison of organ weights between treated and untreated animals have traditionally been used to predict potential toxicity for patients. The manner of presentation of organ weight data, and the value of statistical analyses have been topics of discussion. Historically, a decision tree approach has been applied for statistical comparison of organ weights which does not control the overall error rate and can lead to different statistical tests being used by chance for identical settings causing confusion. This paper proposes a simple nonparametric approach for assessing treatment effects on organ weights in terms of ratios based on the Hodges-Lehmann estimator. This allows for simple interpretation of results and aids in the identification of potential target organs as the evaluation is based on effect sizes and not on p-values allowing a robust proof of effect as well as a robust proof of no effect. The proposed estimate and the corresponding nonparametric confidence interval applied to a rank-sum score can be used as a confirmatory test for difference and as a confirmatory test for equivalence. Exploratory analyses can be performed calculating the proposed estimates for each organ separately to be summarized graphically in a confidence interval plot.

Rate and time to develop first central line-associated bloodstream infections when comparing open and closed infusion containers in a Brazilian Hospital.

The objective of the study was to determine the effect of switching from an open (glass or semi-rigid plastic) infusion container to a closed, fully collapsible plastic infusion container (Viaflex) on rate and time to onset of central lineassociated bloodstream infections (CLABSI). An open-label, prospective cohort, active healthcare-associated infection surveillance, sequential study was conducted in three intensive care units in Brazil. The CLABSI rate using open infusion containers was compared to the rate using a closed infusion container. Probability of acquiring CLABSI was assessed over time and compared between open and closed infusion container periods; three-day intervals were examined. A total of 1125 adult ICU patients were enrolled. CLABSI rate was significantly higher during the open compared with the closed infusion container period (6.5 versus 3.2 CLABSI/1000 CL days; RR=0.49, 95%CI=0.26- 0.95, p=0.031). During the closed infusion container period, the probability of acquiring a CLABSI remained relatively constant along the time of central line use (0.8% Days 2-4 to 0.7% Days 11-13) but increased in the open infusion container period (1.5% Days 2-4 to 2.3% Days 11-13). Combined across all time intervals, the chance of a patient acquiring a CLABSI was significantly lower (55%) in the closed infusion container period (Cox proportional hazard ratio 0.45, p= 0.019). CLABSIs can be reduced with the use of full barrier precautions, education, and performance feedback. Our results show that switching from an open to a closed infusion container may further reduce CLABSI rate as well as delay the onset of CLABSIs. Closed infusion containers significantly reduced CLABSI rate and the probability of acquiring CLABSI.

Itraconazole IV nanosuspension enhances efficacy through altered pharmacokinetics in the rat.

The goal of this research was to evaluate an intravenous itraconazole nanosuspension dosage form, relative to a solution formulation, in the rat. Itraconazole was formulated as a nanosuspension by a tandem process of microcrystallization followed by homogenization. Acute toxicity, pharmacokinetics, and distribution were studied in the rat, and compared with a solution formulation of itraconazole. Efficacy was studied in an immunocompromised rat model, challenged with a lethal dose of either itraconazole-sensitive or itraconazole-resistant C. albicans. Itraconazole nanosuspension was tolerated at significantly higher doses compared with a solution formulation. Pharmacokinetics of the nanosuspension were altered relative to the solution formulation. C(max) was reduced and t(1/2) was much prolonged. This occurred due to distribution of the nanosuspension to organs of the monocyte phagocytic system (MPS), followed by sustained release from this IV depot. The higher dosing of the drug, enabled in the case of the nanosuspension, led to higher kidney drug levels and reduced colony counts. Survival was also shown to be superior relative to the solution formulation. Thus, formulation of itraconazole as a nanosuspension enhances efficacy of this antifungal agent relative to a solution formulation, because of altered pharmacokinetics, leading to increased tolerability, permitting higher dosing and resultant tissue drug levels.